Field of the Invention
The present invention relates to a composition for enhancing drug delivery, imaging resolution and/or affinity. More specifically, the present invention relates to a composition comprising mono-protected Boc-dendrimers and their conjugates.
Description of the Related Art
Cancer continues to be a significant health problem in our society and the number of cases per year is increasing as the population ages. Cancer is likely to impact 1 in 3 of us. According to the American Cancer Society's annual cancer statistics report, “Cancer Statistics, 2013,” 1.6 million Americans will be diagnosed with invasive cancer in 2013, and 0.5 million Americans will die from cancer this year. Cytotoxic agents are currently the major chemotherapeutic treatment modality for most types of cancer. However, current cancer chemotherapeutic treatments remain inherently toxic and have severe side effects.
The role of magnetic resonance imaging (MRI) in the diagnosis and evaluation of cancer continues to evolve and become important because it is non-invasive and non-irradiating. See Bulte et al. “Magnetic resonance microscopy and histology of the CNS,” Trends in Biotechnology, 2002, 20, S24-S28. Although images of tissues can be obtained, contrast agents significantly improve MRI resolution. A current FDA-approved MRI contrast agent is Gd-DTPA, commercialized as MAGNEVIST® gadopentetate dimeglumine Caravan et al. reported other Gd-chelates that are under development, see Caravan et al. “Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications,” Chem. Rev. 1999, 99, 2293-2352. Similar to chemotherapeutic agents, currently approved contrast agents are also nonselective.
The folate-receptor (FR) is overexpressed on a number of major malignancies including adenocarcinoma of the lung and ovarian cancer, see Pribble P, Edelman M J. EC145: a novel targeted agent for adenocarcinoma of the lung. Expert Opin Investig Drugs. 2012; 21(5):755-61. However, relatively few small molecule drug conjugates with folic acid have been investigated since Dr. Fuchs's group at University of Purdue reported that Taxol-folic acid conjugates failed to demonstrate selective killing of folate receptor-expressing tumor cells in vitro or enhanced in vivo antitumor activity over Taxol when administered in an equimolar quantity formulated in the same injection vehicle. See Lee J W, Lu J Y, Low P S, Fuchs P L. Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. Bioorg Med Chem. 2002, 10, 2397-414.
U.S. Pat. No. 7,128,893 disclosed vitamin-targeted imaging agents coupled via a divalent linker (vitamin-linker-imaging agent); U.S. Pat. No. 7,601,332 disclosed a vitamin-targeted drug delivery conjugate via a divalent linker (vitamin-linker-drug).
Relatively few multi-valent linker platforms have been reported. See the following U.S. patents: U.S. Pat. No. 4,435,548; U.S. Pat. No. 4,507,466; U.S. Pat. No. 4,558,120; U.S. Pat. No. 4,568,737; U.S. Pat. No. 4,587,329; U.S. Pat. No. 4,871,779; U.S. Pat. No. 4,631,337. U.S. Pat. No. 5,714,166, disclosed bioactive and/or targeted dendrimer conjugates. However, when a drug is conjugated to a dendrimer and followed by conjugation of a vitamin, a number of species result because it is difficult to control the location and the amount of the drug and the vitamin on the dendrimer. See Majoros I J, Myc A, Thomas T, Mehta C B, Baker J R. PAMAM Dendrimer-Based Multifunctional Conjugate for Cancer Therapy: Synthesis, Characterization, and Functionality. Biomacromolecules 2006, 7, 572-579.
Despite billions of dollars poured every year into developing better treatment options, there is an urgent need for safer and more effective therapies.